Drug discrimination has become one of the most powerful methods available for studying the internal stimuli produced by drugs of abuse. Most drug-discrimination research has focused on the discriminative stimulus effects of single drugs; however, there is extensive evidence that many drug users combine two or more abused drugs. The combined administration of two or more drugs has been investigated on only a small minority of drug-discrimination studies because the behavioral technology available has limited the number of choices that the subject can make in reporting the stimulus effects of drugs to two or three choices. During the previous project period, we have developed an innovative new four-choice procedure for the study of drug discrimination that allows animals to discriminate among two different drugs, a mixture of these two drugs, and the absence of the mixture and either of the drugs in the mixture during a single test session. This procedure should enhance both the sensitivity and the selectivity of the drug-discrimination process for comparing the effects of drug mixtures to the effects of each of the drugs in the mixture. The four-choice procedure will be used to study interactions between morphine and pentobarbital, between dizocilpine and pentobarbital, between methadone and aiprazolam, and between other drug mixtures. The data should provide important evidence about how these drug mixtures interact to produce their effects on the central nervous system. The four-choice procedure should also be very useful for studying the effects of drugs, such as ethanol, that interact with several subclasses of receptors. By training subjects to discriminate among ethanol, that dizocilpine, and pentobarbital, and then studying the discriminative stimulus effects of mixtures of dizocilpine and pentobarbital, it may be possible to delineate the relative contributions of GABA and NMDA receptor interactions to the discriminative stimulus properties of ethanol. Similar types of experiments will be done to determine the role of mu, kappa and delta opioid receptors to the discriminative stimulus effects of opioid drugs that produce complex actions mediated by interactions at several receptor sites.